Reperfusion protection in resuscitation

ABSTRACT

An apparatus and method for resuscitating a patient suffering from cardiac arrest or another condition in which normal circulation has been interrupted. A ventilator is used for delivering a gas mixture to the patient. The ventilator is configured to adjust the partial pressure of CO2 to one or more partial pressures high enough to slow expiration of CO2 from the patient&#39;s lungs and thereby maintain a reduced pH in the patient&#39;s tissues for a period of time following return of spontaneous circulation.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of, and claims priority to,U.S. application Ser. No. 13/020,096, filed on Feb. 3, 2011, which is adivisional application of and claims priority to U.S. application Ser.No. 11/339,307, filed on Jan. 24, 2006, each of which is incorporated byreference herein in its entirety for all purposes.

TECHNICAL FIELD

This invention relates to ventilatory support devices for use in cardiacarrest.

BACKGROUND

Cardiac Arrest, or Sudden Death, is a descriptor for a diversecollection of physiological abnormalities with a common cardiacaetiology, wherein the patient typically presents with the symptoms ofpulselessness, apnoea, and unconsciousness. Cardiac arrest iswidespread, with an estimated 300,000 victims annually in the U.S. aloneand a similar estimate of additional victims worldwide. Earlydefibrillation is the major factor in sudden cardiac arrest survival.There are, in fact, very few cases of cardiac arrest victims saved whichwere not treated with defibrillation. There are many different classesof abnormal electrocardiographic (ECG) rhythms, some of which aretreatable with defibrillation and some of which are not. The standardterminology for this is “shockable” and “non-shockable” ECG rhythms,respectively. Non-shockable ECG rhythms are further classified intohemodynamically stable and hemodynamically unstable rhythms.Hemodynamically unstable rhythms are those which are incapable ofsupporting a patient's survival with adequate blood flow (non-viable).For example, a normal sinus rhythm is considered non-shockable and ishemodynamically stable (viable). Some common ECG rhythms encounteredduring cardiac arrest that are both non-shockable and hemodynamicallyunstable are: bradycardia, idioventricular rhythms, pulseless electricalactivity (PEA) and asystole. Bradycardias, during which the heart beatstoo slowly, are non-shockable and also possibly non-viable. If thepatient is unconscious during bradycardia, it can be helpful to performchest compressions until pacing becomes available. Idioventricularrhythms, in which the electrical activity that initiates myocardialcontraction occurs in the ventricles but not the atria, can also benon-shockable and non-viable (usually, electrical patterns begin in theatria). Idioventricular rhythms typically result in slow heart rhythmsof 30 or 40 beats per minute, often causing the patient to loseconsciousness. The slow heart rhythm occurs because the ventriclesordinarily respond to the activity of the atria, but when the atria stoptheir electrical activity, a slower, backup rhythm occurs in theventricles. Pulseless Electrical Activity (PEA), the result ofelectro-mechanical dissociation (EMD), in which there is the presence ofrhythmic electrical activity in the heart but the absence of myocardialcontractility, is non-shockable and non-viable and would require chestcompressions as a first response. Asystole, in which there is neitherelectrical nor mechanical activity in the heart, cannot be successfullytreated with defibrillation, as is also the case for the othernon-shockable, non-viable rhythms. Pacing is recommended for asystole,and there are other treatment modalities that an advanced life supportteam can perform to assist such patients, e.g. intubation and drugs. Theprimary examples of shockable rhythms that can be successfully treatedwith defibrillation are ventricular fibrillation, ventriculartachycardia, and ventricular flutter.

Normally, electrochemical activity within a human heart causes theorgan's muscle fibers to contract and relax in a synchronized manner.This synchronized action of the heart's musculature results in theeffective pumping of blood from the ventricles to the body's vitalorgans. In the case of ventricular fibrillation (VF), however, abnormalelectrical activity within the heart causes the individual muscle fibersto contract in an unsynchronized and chaotic way. As a result of thisloss of synchronization, the heart loses its ability to effectively pumpblood. Defibrillators produce a large current pulse that disrupts thechaotic electrical activity of the heart associated with ventricularfibrillation and provides the heart's electrochemical system with theopportunity to re-synchronize itself. Once organized electrical activityis restored, synchronized muscle contractions usually follow, leading tothe restoration of effective cardiac pumping.

First described in humans in 1956 by Dr. Paul Zoll, transthoracicdefibrillation has become the primary therapy for cardiac arrest,ventricular tachycardia (VT), and atrial fibrillation (AF). Monophasicwaveforms dominated until 1996, when the first biphasic waveform becameavailable for clinical use. Attempts have also been made to use multipleelectrode systems to improve defibrillation efficacy. While biphasicwaveforms and multiple-electrode systems have shown improved efficacyrelative to monophasic defibrillation, there is still significant roomfor improvement: shock success rate for ventricular fibrillation (VF)remains less than 70% even with the most recent biphasic technology. Inthese cases, shock success was defined to be conversion of a shockablerhythm into a non-shockable rhythm, including those non-shockablerhythms which are also non-viable. Actual survival-to-hospital-dischargerates remain an abysmal ten percent or less. Survival rates from cardiacarrest remain as low as 1-3% in major U.S. cities, including those withextensive, advanced prehospital medical care infrastructures.

Approximately 40-50% of cardiac arrest victims are resuscitated byparamedics and emergency medical technicians (EMTs) in the field andbrought to the hospital for further treatment; however, due to theinsult on the victim's vital organs from the cardiac arrest, typicallyonly about 25% (or approximately 40,000 out of 600,000 cardiac arrestvictims, worldwide) of those victims who survive to the hospital willsurvive to being discharged from the hospital.

The treatment window for cardiac arrest with current treatments ofdefibrillation, cardiopulmonary resuscitation, and inotropic (e.g.epinephrine) drug treatment is very narrow. Long term survival ratesfrom the time of victim collapse decrease at a roughly exponential ratewith a time constant of roughly 2 minutes. Thus, just two minutes ofdelay in treatment using the currently recommended treatment protocolsresult in a long term survival rate of 30-35%. After 15 minutes, thelong term survival rates are below 5%. While the response times ofemergency medical systems have improved significantly over the lastquarter century to the point that average times from emergency call toarrival at the victim is typically 9 minutes or less, bystander delaysin making the emergency call typically add 2-3 minutes to the totalarrest time, for a total of 11-12 minutes. In addition, the bystandermaking the emergency call may not even have witnessed the cardiacarrest, which may have occurred at some point in the past. Unwitnessedarrest accounts for at least half of all cardiac arrests. Cardiac arrestdowntimes are only reported for witnessed arrests; it has beenestimated, however, that if unwitnessed arrests were to be included, theaverage downtime for all victims would exceed 15 minutes. At the time ofinitial collapse, the ECGs of nearly all cardiac arrest victims areshockable rhythms such as VF or VT; after 15 minutes, however, the ECGrhythms of most cardiac arrest victims have degenerated into thenon-shockable rhythms of PEA or asystole. Attempts to reduce thisresponse time through the widespread adoption of AEDs has been minimallysuccessful, at best, for a variety of economic and social factors. Itwould be thus advantageous to have treatment methods available to dealwith cardiac arrest victims with profound ischemia due to longdowntimes.

During cardiac arrest, cerebral blood flow ceases and global cerebralhypoxic-ischemic injury begins within minutes. Myocardial and neuronaltissue is able to remain viable during prolonged periods of ischemia—aslong as twenty minutes, but paradoxically will sustain immediate damageduring the return of circulation and oxygenation. It has been shown in avariety of studies at the tissue-level and animal model that successfulresuscitation with return of spontaneous circulation (ROSC) leads to asecondary cascade of injury related to reperfusion injury. Thisreperfusion injury is particularly acute in neuronal tissue. Whenneurons and myocytes shift to anaerobic metabolism as a result of oxygendepletion, during the course of ATP hydrolysis lactate is converted tolactic acid, H+ is generated, and intracellular pH drops. This activatesthe sodium/hydrogen (NaH) exchange ion channels, which, however, requireATP and thus become depressed during ischemia. There is thus a build-upof intracellular H+ during ischemia. During reperfusion, the NaHexchange channel is reactivated causing a net influx of sodium whichthen causes a net influx of calcium via the sodium/calcium (NCX)exchange channel in order to exteriorize the elevated sodium ions.Elevation of intracellular calcium can lead to an accumulation of thision by mitochondria, with activation of mitochondrial permeabilitytransition (MPT).

During reperfusion, intracellular levels of glutamate, an excitatoryneurotransmitter released from presynaptic terminals, increasesmarkedly. Glutamate activates ion channel complexes, particularly theN-methyl-D-aspartate (NMDA) receptors, which when activated increasecalcium conductance from the extracellular to intracellular fluid.Mitochondrial calcium increases, resulting in the formation of reactiveoxygen species. Both mitochondrial calcium overload and ROS productioninitiate the formation of large pores in the mitochondrial membrane.Opening of high-conductance mitochondrial transition pores (MTP) in themitochondrial inner membrane initiates onset of the mitochondrialpermeability transition (MPT). The MTP pores conduct both positively andnegatively charged solutes of up to 1,500 Da. Pore opening causes thecollapse of mitochondrial membrane potential and cessation ofmitochondrial ATP production. In addition, multiple biochemical cascadeslead to the production of oxygen free-radicals and the activation ofproteases, endonucleases, phospholipases and xanthine oxidase whichcause destruction of cell membranes and other essential cytoskeletalstructures such as microtubules. Even if these events are notimmediately fatal to the cell, some neurons later undergo programmedcell death (apoptosis).

After successful cardiac resuscitation and ROSC, cerebral blood flow mayremain abnormally low for several hours. After an initial hyperemiaresulting from high circulating levels of catecholamines, cerebral bloodflow decreases just as the cerebral metabolic rate for oxygen increases.This can lead to a prolonged state of relative cerebral ischemia. Thisprolonged mismatch between cerebral metabolic rate and blood flow, andongoing biochemical and molecular processes related to delayed neuronalapoptotic and necrotic cell death, provide the scientific rationale forinduced hypothermia as a form of neuroprotection after cardiac arrest.One method developed is the cooling of comatose cardiac arrest survivorsto approximately 34 degrees Celsius within 4 hours of arrest onset. Theexact mechanism for the therapeutic effects of hypothermia is not fullyunderstood, but has been shown in several studies to enhance thesurvival rates of patients who are initially resuscitated (theapproximately 40-50% of victims making it to the hospital). Hypothermiais common in the cardiac intensive care, hospital environment such as inbypass operations, etc, but there are two related drawbacks ofhypothermia which have prevented its widespread use in the pre-hospitalenvironment.

The first of these drawbacks is the primary biomedical engineeringchallenge of hypothermia: the large thermal mass of the victim and thedifficulty of cooling the victim quickly and safely. While it has beenshown that hypothermia is beneficial as long as it is applied within 4hours of cardiac arrest, studies have also shown that cooling prior toresuscitation provides additive therapeutic benefits. While the causesfor this are only speculative, one of the factors is likely the positiveeffects of hypothermia during the reperfusion phase of resuscitation.Practically speaking, it is highly undesirable to delay defibrillationand resuscitation to cool a patient to the proper temperature.Non-invasive methods of cooling take at minimum 10 minutes to 1 hour,while invasive methods such as extraction and cooling of the blood maytake only 3-5 minutes, but are hazardous to the patient, particularly inthe pre-hospital environment. In the case of defibrillation, even adelay of 3 minutes can result in a decrease in survival of 30%. Whilehypothermia may be effective at counteracting longer-term deleteriouseffects of ischemia and reperfusion, it would be desirable to have atreatment that can provide immediate protective effects againstreperfusion injury while, at the same time, not delaying any currentresuscitation interventions.

The mechanisms allowing prolonged cell survival during ischemia andminimizing lethal cell injury after reperfusion remain incompletelyunderstood. It has been shown in studies that the naturally occurringacidosis of ischemia, like hypothermia, strongly protects renal cells,myocytes, and hepatocytes against ischemia-induced cell death. Incontrast, the return of extracellular pH to physiological levels is anevent that actually precipitates lethal cell injury, termed the “pHparadox”. It has been hypothesized by researchers that the pH dependencyof reperfusion injury may be the consequence of the pH dependency of theMTP opening. Conductance of the NMDA channel is also known to decreasesteeply when extracellular pH is reduced below 7.0. Intracellular pH mayalso be important; intracellular acidosis during and after simulatedischemia and reperfusion has been shown to protect cultured cardiacmyocytes against injury. Increased extracellular proton concentrationwill also minimize the inward sodium influx via the Na—H exchange ionchannels, thereby reducing the intracellular sodium concentrations andthe net influx of calcium via the sodium-calcium exchanger channels, andthus minimizing calcium overload.

Ventilation is a key component of cardiopulmonary resuscitation duringtreatment of cardiac arrest. Venous blood returns to the heart from themuscles and organs depleted of oxygen (O₂) and full of carbon dioxide(CO₂). Blood from various parts of the body is mixed in the heart (mixedvenous blood) and pumped to the lungs. In the lungs the blood vesselsbreak up into a net of small vessels surrounding tiny lung sacs(alvcoli). The net sum of vessels surrounding the alveoli provides alarge surface area for the exchange of gases by diffusion along theirconcentration gradients. A concentration gradient exists between thepartial pressure of CO₂ (PCO₂) in the mixed venous blood (PvCO₂) and thealveolar PCO₂. The CO₂ diffuses into the alveoli from the mixed venousblood from the beginning of inspiration until an equilibrium is reachedbetween the PvCO₂ and the alveolar PCO₂ at some time during the breath.When the subject exhales, the first gas that is exhaled comes from thetrachea and major bronchi which do not allow gas exchange and thereforewill have a gas composition similar to the inhaled gas. The gas at theend of this exhalation is considered to have come from the alveoli andreflects the equilibrium CO₂ concentration between the capillaries andthe alveoli; the PCO₂ in this gas is called end-tidal PCO₂ (PE_(t)CO₂).

When the blood passes the alveoli and is pumped by the heart to thearteries it is known as the arterial PCO₂ (PaCO₂). The arterial bloodhas a PCO₂ equal to the PCO₂ at equilibrium between the capillaries andthe alveoli. With each breath some CO₂ is eliminated from the lung andfresh air containing little or no CO₂ (CO₂ concentration is assumed tobe 0) is inhaled and dilutes the residual alveolar PCO₂, establishing anew gradient for CO₂ to diffuse out of the mixed venous blood into thealveoli. The rate of breathing, or minute ventilation (V), usuallyexpressed in L/min, is exactly that required to eliminate the CO₂brought to the lungs and maintain an equilibrium PCO₂ (and PaCO₂) ofapproximately 40 mmHg (in normal humans). When one produces more CO₂(e.g., as a result of fever or exercise), more CO₂ is produced andcarried to the lungs. One then has to breathe harder (hyperventilate) towash out the extra CO₂ from the alveoli, and thus maintain the sameequilibrium PaCO₂. But if the CO₂ production stays normal, and onehyperventilates, then the PaCO₂ falls. Conversely, if CO₂ productionstays constant and ventilation falls, arterial PCO₂ rises. Some portionof the inspired air volume goes to the air passages (trachea and majorbronchi) and alveoli with little blood perfusing them, and thus doesn'tcontribute to removal of CO₂ during exhalation. This portion is termed“dead space” gas. That portion of V that goes to well-perfused alveoliand participates in gas exchange is called the alveolar ventilation (VA)and exhaled gas that had participated in gas exchange in the alveoli istermed “alveolar gas”.

Monitoring and control of ventilation parameters as a function ofmeasured expiratory CO₂ is commonly used in ventilation systems. U.S.Pat. No. 4,112,938 describes a respirator that uses measurement ofalveolar gas CO₂ partial pressure as a means of adjusting a reservoirsize to control inspiratory CO₂ concentration. U.S. Pat. No. 5,320,093describes a ventilator that adjusts inspiratory CO₂ concentration so asto enhance a patient's natural ventilatory drive during recovery fromanesthesia. In U.S. Pat. No. 5,402,796, a method is described whichprovides better accuracy of PaCO₂ utilizing an initial calibrationsample. U.S. Pat. Nos. 5,778,872, 6,612,308B2 and 6,799,570B2 portableventilators that use reservoirs to store exhaled air for later use inrebreathing during inspiration so as to keep CO₂ levels constant(“isocapnia”). U.S. Pat. No. 6,612,308B2 is further refined in U.S. Pat.No. 6,622,725B1 by providing a method for separating out the alveolargas from the dead space gas, thus concentrating the expiratory CO₂ forlater rebreathing. U.S. Pat. No. 6,951,216B2 describes a ventilatorutilizing a space-efficient CO₂ exchanger that absorbs and storesexpiratory CO₂ gas that is later released into the inpsiratory gasstream to enhance CO₂ concentrations.

SUMMARY

In general, the invention features an apparatus and method forresuscitating a patient suffering from cardiac arrest or anothercondition in which normal circulation has been interrupted. A ventilatoris used for delivering a gas mixture to the patient. The ventilator isconfigured to adjust the partial pressure of CO2 to one or more partialpressures high enough to slow expiration of CO2 from the patient's lungsand thereby maintain a reduced pH in the patient's tissues for a periodof time following return of spontaneous circulation.

In preferred implementations, one or more of the following features maybe incorporated. The partial pressure of CO₂ may be adjusted to behigher than ambient CO₂ partial pressure during the period of time.Adjustment of the partial pressure of CO₂ may include adding CO₂ to thegas inspired by the patient. The apparatus may comprise a sensor andassociated processing for measuring a physiological status of thepatient, wherein the partial pressure of CO₂ may be adjusted at least inpart in response to the output of the sensor. The sensor and associatedprocessing may be configured to detect return of spontaneouscirculation, and wherein the partial pressure of CO₂ may be changed inresponse to detection of return of spontaneous circulation. The periodof time may be greater than 30 seconds. The period of time may begreater than 3 minutes. The sensor may comprise a CO₂ sensor. Adjustmentof the partial pressure of CO₂ may have the effect of maintaining the pHof the patient's tissues below 7.0 for the period of time followingreturn of spontaneous circulation. The pH of the patient's tissues maybe maintained below 6.8. The pH of the patient's tissues may bemaintained below 6.5. The apparatus may further comprise adefibrillator, a chest compressor, an infuser, and/or a sensor andassociated processing for determining the pH of the patient's tissue,wherein the partial pressure of CO₂ may be adjusted at least in part inresponse to the pH of the patient's tissue. The partial pressure of CO₂may be adjusted to maintain tissue pH below 6.8 for a period of timefollowing return of spontaneous circulation. The partial pressure of CO₂may be gradually lowered over at least a portion of the period of timeso as to gradually raise the pH of the patient's tissues. The apparatusmay further comprise processing using a mathematical model of therelationship between CO₂ retention in the patient and the pH of thepatient's tissues. The mathematical model may comprise processing usingthe Henderson-Hasselbalch equations. The apparatus may further compriseapparatus and processing for measuring the inspired volume and expiredvolume of CO₂ in the ventilation cycle, and using the inspired andexpired volumes to adjust the partial pressure of CO₂ and apparatus andprocessing for monitoring an E_(t)CO₂ level, and wherein the partialpressure of CO₂ may be adjusted to maintain the E_(t)CO₂ level above alevel found in the arrest victim prior to the arrest. The adjustment ofthe partial pressure of CO₂ may be accomplished by adjusting the partialpressure between a lower level in a first cycle and a higher level in asecond cycle, wherein in the first cycle the partial pressure of CO₂ maybe lower than a previously measured E_(t)CO₂ level, and wherein in thesecond cycle the partial pressure of CO₂ may be higher than thepreviously measured E_(t)CO₂ level, and wherein the lower and higherlevels may be adjusted to maintain E_(t)CO₂ at a desired level. Theventilator and chest compressor may be controlled so that a ratio ofchest compression rate to ventilation rate is less than 15:2 during atleast a portion of the period of time following return of spontaneouscirculation. The ratio may be less than 5:1. The ratio may be about 6:2.The apparatus may further comprise a fluid infusion device. The fluidinfusion device may be configured to infuse fluids containing metabolicsubstances during reperfusion. The metabolic substances may compriseamino acids. The amino acids may comprise aspartate, dihydroxyacetonephosphate or glutamate. The apparatus may further comprise adefibrillator, compressor, and infuser. The defibrillator, compressor,ventilator, and infuser may be separate devices and may be linked by acommunications link. An additional computing device may be used tosynchronize all of the separate devices. There may be both negative andpositive pressures available from the ventilator. The ventilator may beconfigured to elevate oxygen levels to greater than 40%. The period oftime may begin prior to the return of spontaneous circulation. Theperiod of time may begin immediately prior to the return of spontaneouscirculation.

Other features and advantages of the invention will be apparent from thedescription and drawings, and from the claims.

DESCRIPTION OF DRAWINGS

FIG. 1 is the system block diagram of one implementation of one aspectof the invention, including a ventilator integrated with a mechanicalchest compression device and a defibrillator.

FIG. 2 is a block diagram of the ventilator if FIG. 1.

FIGS. 3A and 3B are plots depicting a typical end-tidal capnographicmeasurement curve.

FIGS. 4A and 4B are plots depicting the end-tidal capnographic curve(dotted line) with elevated levels of inspired CO₂.

FIG. 5 is a block diagram of a gas mixture control loop of theimplementation of FIG. 1.

DETAILED DESCRIPTION

There are a great many different implementations of the inventionpossible, too many to possibly describe herein. Some possibleimplementations that are presently preferred are described below. Itcannot be emphasized too strongly, however, that these are descriptionsof implementations of the invention, and not descriptions of theinvention, which is not limited to the detailed implementationsdescribed in this section but is described in broader terms in theclaims.

Some implementations may reduce reperfusion injury by maintaining a lowtissue pH during the time period immediately prior to and from 0-60minutes subsequent to the return of spontaneous circulation (ROSC) bymeans of addition of carbon dioxide to the inspiratory gases while atthe same time increasing oxygen content relative to normal room airconcentrations to enhance oxygenation of the brain, heart and othervital organs.

Referring to FIGS. 1 and 2, the block diagram in FIG. 1 shows anintegrated resuscitation system (IRS) with components designed toaddress various aspects of a resuscitation: defibrillator 13, mechanicalcompressor 12, and ventilator 15. By control of the partial pressures ofthe ventilation gases (particularly oxygen), ambient air, and carbondioxide via the mixing valves 35, the IRS can maintain a patient'stissue pH at approximately the below normal level present immediatelyprior to ROSC.

The tissue pH is controlled by the following well known physiologicalmechanism. The transport of CO₂ can have a significant impact on theacid-base status of the blood and tissues. The lung excretes over 10,000molar equivalents of carbonic acid per day compared to less than 100molar equivalent of fixed acids by the kidneys. Therefore, by alteringalveolar ventilation and the elimination of CO₂, the acidity of thetissues of the brain, heart, gut and other organs can be modified. CO₂is carried in the blood in three forms: dissolved, as bicarbonate, andin combination with proteins such as carbamino compounds. In solution,carbon dioxide hydrates to form carbonic acid:CO₂+H₂O

H₂CO₃

The largest fraction of carbon dioxide in the blood is in the form ofbicarbonate ion, which is formed by ionization of carbonic acid:H₂CO₃

H⁺+HCO₃

2H⁺+CO₃ ²⁻

Using the law of mass action, the Henderson-Hasselbalch equation isderived:[H⁺]=K₁′[H₂CO₃]/[HCO₃ ⁻],or[H+]=K′(αP_(CO2))/[HCO₃ ⁻],where α P_(CO2) is the total concentration of CO₂ and H₂CO₃. The logform of the Hasselbalch equation takes the form:pH=pK_(A)+log(HCO₃ ⁻)/(0.03 P_(CO2)),where K_(A) is the dissociation constant of carbonic acid, equal to 6.1.

Normal HCO₃ ⁻ concentration is 24 mmol/liter, with a resultant pH of7.4. During total ischemia induced by cardiac arrest or trauma, pH willfall to below 7, and commonly in the range of 6.5-6.8, as a result ofincreasing levels of CO₂. At the resumption of circulation and gasexchange in the alveoli, the end-tidal carbon dioxide (E_(t)CO₂) value,as measured by the commonly used capnograph or capnometer, increasesrapidly from a value typically below 10 mmHg found during arrest to asupranormal value of 50-75 mmHg—normal values are approximately 35mmHg—as the body attempts to reduce its CO₂ levels.

Referring to FIGS. 3A and 3B, phase I represents airway dead space. Itis the CO₂-free portion of the exhaled breath from the conductingairways. Phase II represents the mixing of airway dead space gas withalveolar gas and is characterized by a significant rise in CO₂. PhaseIII represents alveolar volume. The plateau reflects the level ofeffective ventilation in the alveoli. Two lines are constructed on thegraph; one on the slope of Phase III and the other such that areas p andq are equal.

Airway dead space is measured from the start of expiration to the pointwhere the vertical line crosses the exhaled volume axis. The volume ofCO₂ in the breath is equal to area X, the total area under the curve.Adding individual breath volumes allows minute CO₂ elimination to becalculated in ml/min. Physiologic Vd/Vt as well as physiologic andalveolar dead space can also be calculated if arterial PCO₂ is known. Aline representing the arterial PCO₂ value is constructed parallel to theexhaled volume axis creating areas Y and Z. Area X represents the volumeof CO₂ in the exhaled tidal volume. Areas Y and Z represent wastedventilation due to alveolar and airway dead space respectively.

Referring to FIGS. 1, 4A and 4B, and the flowchart in FIG. 5, theprocessing unit 14, made up of an electronic processor such as amicroprocessor as well as memory and support logic, first determinesthat a cardiac arrest is in progress, by one or a combination of suchknown techniques as: (1) electrocardiographic (ECG) analysis todetermine whether the ECG is a rhythm due to ventricular fibrillation,ventricular tachycardia, PEA or asystole or a rhythm of supraventricularorigin such as a normal sinus rhythm; (2) analysis of the transthoracicimpedance signal to determine whether there is blood flow; or (3) simplyby means of an input via the user interface 6 by the rescuer 5indicating that an arrest is in progress. If an arrest is determined tobe in progress, the inspiratory gas mixture is adjusted viaelectronically-controlled flow valves 35 in the differential flowcontrol (DFC) subunit to be predominantly oxygen (60-100%). Once in theCARDIAC ARREST state, the processing unit 14 will wait for input thatdefines ROSC. This input may be as simple as an input via the userinterface by the rescuer that ROSC has occurred, though preferably theinput includes a capnometric signal measuring end tidal CO₂ (E_(t)CO₂)values 2 in the expired air. When the processing unit 14 detects anincrease of more than 30% of the baseline cardiac arrest E_(t)CO₂ valuein 30 seconds and a value greater than 25 mmHg, the processing unit 14will enter the ROSC state, and begin the process of adding CO₂ to theinspired gas mixture.

In other implementations, either the tissue CO₂ or pH are measured bysuch methods as disclosed in U.S. Pat. No. 6,055,447, which describes asublingual tissue CO₂ sensor, or U.S. Pat. Nos. 5,813,403; 6,564,088;and 6,766,188; which describe a method and device for measuring tissuepH via near infrared spectroscopy (NIRS). Each of these patents (U.S.Pat. Nos. 6,055,447; 5,813,403; 6,564,088; and 6,766,188) is herebyexpressly incorporated herein by reference in its entirety for allpurposes. NIRS technology allows the simultaneous measurement of tissuePO₂, PCO₂, and pH. One drawback of previous methods for the measurementof tissue pH is that the measurements provided excellent relativeaccuracy for a given baseline measurement performed in a series ofmeasurements over the course of a resuscitation, but absolute accuracywas not as good, as a result of patient-specific offsets such as skinpigment. One of the benefits of the currently-described implementationsis that they do not require absolute accuracy of these pH measurements,only that the offset and gain be stable over the course of theresuscitation. Because tissue pH responds slowly over the course ofmultiple ventilation cycles, it is used primarily to augment control ofE_(t)CO₂ levels by adjusting CO_(2i) with the goal of regulating tissuepH per the following regimen: (1) during the first 5 minutes followingROSC, the pH should remain flat; (2) during the time period of 5-10minutes, the tissue pH should increase no more than 0.4 pH units/minute,and should be limited to not increase above an absolute number of 6.8;and (3) during the 10-15 minute time period, if the pH is still lessthan 6.8, CO_(2i) is adjusted to allow pH to increase at a rate ofapproximately 0.4 pH units/minute, and if tissue pH is greater than 7then CO_(2i) is adjusted to a slower rate of 0.2 pH units/minute.

Referring to FIG. 2, the ventilator provides for both negative andpositive pressures by means of the double venturi 32 such as thatdescribed in U.S. Pat. No. 5,664,563. Safety mechanisms are provided byshutoff valve 31 and exhaust valve 28. Heater/humidifier element 33conditions the gas prior to entering the inspiration circuit, andcapnometric measurements are determined using the capnometric sensor 22and tidal volume sensor 21.

Referring again to FIGS. 3A and 3B, by measuring both flow rates and theCO₂ concentration (partial pressure), the quantity of CO₂ for theinspiration and expiration cycle can be tracked by integrating the CO₂flow. Though the amount of excess CO₂ may be unknown, the amount of CO₂transferred from the bloodstream to the alveoli can be accuratelycontrolled by measuring the difference in CO₂ volume on the inspired andexpired cycles. Thus to achieve constant CO₂ levels, CO₂ is increased tothe level such that the volumes of CO₂ on inspired and expired cyclesare equal. Volumetric measurements for the inspired and expired cyclesmay be averaged over several cycles to increase accuracy.

In other implementations, either the tissue CO₂ or pH are measured bysuch methods as disclosed in U.S. Pat. No. 6,055,447, which describes asublingual tissue CO₂ sensor, or U.S. Pat. Nos. 5,813,403; 6,564,088;and 6,766.188; which describe a method and device for measuring tissuepH via near infrared spectroscopy (KIRS). Each of these patents (U.S.Pat. Nos. 6,055,447; 5,813,403; 6,564,088; and 6,766,188) is herebyexpressly incorporated herein by reference in its entirety for allpurposes. NIRS technology allows the simultaneous measurement of tissuePO₂, PCO₂ and pH. One drawback of previous methods for the measurementof tissue pH is that the measurements provided excellent relativeaccuracy for a given baseline measurement, performed in a series ofmeasurements over the course of a resuscitation, but absolute accuracywas not as good, as a result of patient-specific offsets such as skinpigment. One of the benefits of the currently-described implementationsis that they do not require absolute accuracy of these pH measurements,only that the offset and gain be stable over the course of theresuscitation. Because tissue pH responds slowly over the course ofmultiple ventilation cycles, it is used primarily to augment control ofE_(t)CO₂ levels by adjusting CO₂ with the goal of regulating tissue pHper the following regimen: (1) during the first 5 minutes followingROSC, the pH should remain flat; (2) during the time period of 5-10minutes, the tissue pH should increase no more than 0.4 pH units/minute,and should be limited to not increase above an absolute number of 6.8;and (3) during the 10-15 minute time period, if the pH is still lessthan 6.8, CO₂ is adjusted to allow pH to increase at a rate ofapproximately 0.4 pH units/minute, and if tissue pH is greater than 7then CO₂ is adjusted to a slower rate of 0.2 pH units/minute.

In some cases, such as cardiac arrest cases with shorter periods ofischemia, it may be desirable to reduce pH levels below the levelspresent in the cardiac arrest victim by augmenting CO₂ levels. In suchcases, pH would be decreased during phase 1 of the regimen described inthe previous paragraph.

Tissue CO₂, and thus pH, as well, are adjusted by increasing ordecreasing inspired CO₂ levels via the CO_(2i) ^(H) and CO_(2i) ^(L)levels; for instance, decreasing both levels will cause additional CO₂to be exhaled, thus reducing tissue pH. Adjustments are made inapproximately 10% increments at approximately 3 times per minute. Thelow update rate of CO_(2i) ^(H) and CO_(2i) ^(L) levels is due to thefact that the time constant for pH changes due to CO_(2i) changes isslow as well.

In other implementations, medical knowledge such as that described inCrit Care Med 2000 Vol. 28, No. 11 (Suppl.) is incorporated into aclosed loop feedback system to augment the methods described above forcontrolling tissue pH during resuscitation. As the author describes, thesystem of differential equations has been described in a number ofpublications. In this specific instance, “the human circulation isrepresented by seven compliant chambers, connected by resistancesthrough which blood may flow. The compliances correspond to the thoracicaorta, abdominal aorta, superior vena cava and right heart, abdominaland lower extremity veins, carotid arteries, and jugular veins. Inaddition, the chest compartment contains a pump representing thepulmonary vascular and left heart compliances. This pump may beconfigured to function either as a heart-like cardiac pump, in whichapplied pressure squeezes blood from the heart itself through the aorticvalve, or as a global thoracic pressure pump, in which applied pressuresqueezes blood from the pulmonary vascular bed, through the left heart,and into the periphery. Values for physiologic variables describing atextbook normal ‘70-kg man’ are used to specify compliances andresistances in the model. The distribution of vascular conductances(1/resistances) into cranial, thoracic, and caudal components reflectstextbook distributions of cardiac output to various body regions.” Inaddition to these equations, implementations may incorporate inspiratoryvolumetric measurement and the universal alveolar airway equation, theHenderson-Hasselbalch equation, and a three-compartment model of carbondioxide storage in the body. The compartment with the lowest timeconstant corresponds to the well-perfused organs of brain, blood,kidneys, heart; the second compartment corresponds to skeletal muscle;and the third compartment corresponds to all other tissue.

Referring to FIG. 5, a closed loop feedback method is employed, usingstate space methods with the system estimation block 55 provided by aphysiological model as described above with augmentations to include CO₂and pH effects. The Feedback Controller 53 may employ such traditionalcontrol system methods as proportional, difference, integral (PID) orstate feedback control methods, known to those skilled in the art.

Since the caiac arrest victim is spontaneously breathing during ROSC,and the central chemoreceptors will be stimulated by the elevated CO₂levels and depressed pH, it is necessary for the ventilator to respondto the victim's own inspiratory efforts. Pressure sensing is used todetermine patient respiratory effort. A combination of synchronizedintermittent mandatory ventilation (SIMV) and inspiratory pressuresupport ventilation (PSV) are used to provide proper responsiveness tovictim respiratory needs while at the same time providing a sufficientamount of minute ventilation so that pCO₂ can be regulated via CO_(2i).SIMV allows the victim to take breaths between artificial breaths andPSV assists the victim in making an inspiration of a pattern that islargely of their own control. With PSV, the amount of support isvariable, with more support being provided in the early stages of ROSCand the support gradually reduced as the victim's status improves duringthe course of ROSC.

The drug infuser 18 may be used to deliver other agents such asglutamate, aspartate or other metabolically active agents that may beparticularly effective during the pH-depressed reperfusion state of theinvention in renormalizing lactate levels and generating the ATP storesnecessary to restore cytosolic calcium homeostasis prior to allowing pHto increase.

The chest compressor 12 and ventilator 15 may be physically separatefrom the defibrillator, and the physiological monitor 10 and control ofthe chest compressor 12 and ventilator 15 may be accomplished by acommunications link 16. The communications link 16 may take the form ofa cable connecting the devices but preferably the link 16 is via awireless protocol such as Bluetooth or a wireless protocol such asInstitute of Electrical and Electronics Engineers (IEEE) 802.11. Theseparate chest compressor 12 and can be a portable chest compressiondevice such as that commercially available as the Autopulse™, providedby ZOLL Circulatory Systems of Sunnyvale Calif. The separate ventilator15 can be a ventilator such as that is commercially available as theIVent™, provided by Versamed of Peal River, N.Y. The separate druginfuser 18 can be a drug infusion device such as that commerciallyavailable as the Power Infuser™, provided by Infusion Dynamics ofPlymouth Meeting, Pa., or the Colleague CX™, provided by BaxterHealthcare Corp., of Round Lake, Ill. The chest compressor 12,ventilator 15, drug infuser 18, and defibrillator 13 can also beintegrated into one housing such as that for the Autopulse™, provided byZOLL Circulatory Systems of Sunnyvale, Calif.

In other implementations, control and coordination for the overallresuscitation event and the delivery of the various therapies may beaccomplished by a device 17 or processing element external to either thechest compressor, ventilator, or defibrillator. For instance the device17 may be a laptop computer or other handheld computer or a dedicatedcomputing device that will download and process the ECG data from thedefibrillator, analyze the ECG signals, perform the determinations basedon the analysis, and control the other therapeutic devices, includingthe defibrillator 13. While the system has been described for cardiacarrest, it is also applicable for trauma victims or other forms ofarrest where the victim is suffering, from amongst other conditions, aglobal ischemia, and resuscitation from which requires the patient totransition through a state of reperfusion.

Many other implementations of the invention other than those describedabove are within the invention, which is defined by the followingclaims. References to “processing” in the claims include amicroprocessor (and associated memory and hardware) executing software.

What is claimed is:
 1. A medical system comprising: at least one sensorconfigured to perform near infrared spectroscopy (NIRS), and to generatea signal representing a pH of tissues of a patient; and a processorcommunicably coupled to the at least one sensor, the processorconfigured to: receive the signal; and generate an instructionconfigured to result in a ventilator adjusting a partial pressure of CO2in a gas mixture delivered to the patient to one or more partialpressures high enough to slow expiration of CO₂ from the patient's lungsand thereby maintain an increased PCO₂ in tissues of the patient for aperiod of time following return of spontaneous circulation (ROSC),wherein the instruction is configured to result in the ventilatoradjusting the partial pressure of the CO₂ in the gas mixture so as tomaintain the pH at a constant level for a first portion of the period oftime following ROSC.
 2. The medical system of claim 1, wherein themedical system comprises the ventilator and wherein the processor iscommunicably coupled to the ventilator and is configured to provide theinstruction to the ventilator.
 3. The medical system of claim 2 furthercomprising valves configured to adjust a mixture of inspiratory gas tothe patient.
 4. The medical system of claim 3 wherein the processor isconfigured to electronically control the valves at least in response toa determination that ROSC has occurred.
 5. The medical system of claim 4wherein the valves are configured to add CO₂ to the mixture ofinspiratory gas based on a determined CO₂ partial pressure adjustment.6. The medical system of claim 1 comprising a display, wherein theprocessor is further configured to control the display to cause theinstruction to be displayed to a clinician.
 7. The medical system ofclaim 1, wherein the at least one sensor comprises an optical sensor. 8.The medical system of claim 1, wherein the instruction is configured toresult in the ventilator adjusting the partial pressure of CO₂ in thegas mixture so as to cause the pH to increase at a first rate during asecond portion of the period of time following ROSC.
 9. The medicalsystem of claim 8, wherein the first rate comprises no more than 0.4 pHunits/minute.
 10. The medical system of claim 8, wherein the instructionis configured to result in the pH increasing during the second portionof the period of time following ROSC such that the absolute value of thepH at an end of the second portion of the period of time following ROSCis no more than 6.8.
 11. The medical system of claim 8, wherein theinstruction is configured to result in the ventilator adjusting thepartial pressure of CO₂ in the gas mixture so as to cause the pH toincrease at a second rate during a third portion of the period of timefollowing ROSC.
 12. The medical system of claim 11, wherein the at leastone sensor is configured to generate the signal representing the pH ofthe tissues of the patient during the third portion of the period oftime following ROSC, and wherein: if the pH during the third portion ofthe period of time following ROSC is less than 6.8, the second ratecomprises approximately 0.4 pH units/minute or less; and if the pHduring the third portion of the period of time following ROSC is greaterthan 7, the second rate comprises approximately 0.2 pH units/minutes orless.
 13. The medical system of claim 11, wherein each of the firstportion, the second portion, and the third portion of the period of timefollowing ROSC comprises up to approximately five minutes.
 14. Themedical system of claim 1 further comprising a user interface configuredto capture input indicating that ROSC has occurred.
 15. The medicalsystem of claim 1 wherein the processor is communicatively coupled to atleast one sensor configured to measure CO₂ concentration in an airway ofthe patient and further wherein the processor is configured to receive,from the at least one sensor configured to measure CO₂ concentration inthe airway of the patient, at least two measurements of the CO₂concentration in the airway of the patient and to determine whether ROSChas occurred based on a comparison of the at least two measurements ofCO₂ concentration in the airway of the patient.
 16. A method ofresuscitating a patient suffering from cardiac arrest or anothercondition in which normal circulation has been interrupted, the methodcomprising: determining, using near infrared spectroscopy (NIRS), a pHof tissues of the patient; and delivering, using a ventilator, a gasmixture to the patient, adjusting, by the ventilator, a partial pressureof CO₂ in the gas mixture to one or more partial pressures high enoughto slow expiration of CO₂ from the patient's lungs and thereby maintainan increased tissue PCO₂ for a period of time following return ofspontaneous circulation (ROSC), wherein the adjusting the partialpressure by the ventilator comprises adjusting the partial pressure ofthe CO₂ in the gas mixture so as to maintain the pH at a constant levelfor a first portion of the period of time following ROSC.
 17. The methodof claim 16, wherein the adjusting the partial pressure by theventilator further comprises adjusting the partial pressure of CO₂ inthe gas mixture so as to cause the pH to increase at a first rate duringa second portion of the period of time following ROSC.
 18. The method ofclaim 17, wherein the first rate comprises no more than 0.4 pHunits/minute.
 19. The method of claim 17, wherein the adjusting thepartial pressure by the ventilator further comprises adjusting thepartial pressure of CO₂ in the gas mixture so as to cause the pH toincrease during the second portion of the period of time following ROSCsuch that the absolute value of the pH at an end of the second portionof the period of time following ROSC is no more than 6.8.
 20. The methodof claim 17, wherein the adjusting the partial pressure by theventilator further comprises adjusting the partial pressure of CO₂ inthe gas mixture so as to cause the pH to increase at a second rateduring a third portion of the period of time following ROSC.
 21. Themethod of claim 20, further comprising determining the pH of the tissuesof the patient during the third portion of the period of time followingROSC, wherein: if the pH during the third portion of the period of timefollowing ROSC is less than 6.8, the second rate comprises approximately0.4 pH units/minute; and if the pH during the third portion of theperiod of time following ROSC is greater than 7, the second ratecomprises 0.2 pH units/minute.
 22. The method of claim 20, wherein eachof the first portion, the second portion, and the third portion of theperiod of time following ROSC comprises five minutes.